Copper catalyzed [18F]fluorination of iodonium salts

ABSTRACT

Copper-catalyzed radiofluorination of iodonium salts, iodonium salts, and compounds obtained by copper-catalyzed radiofluorination of iodonium salts are disclosed. Diagnostic and therapeutic methods involving such compounds also are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national phase of PCT/US2015/25241, filedApr. 10, 2015, which claims the benefit of U.S. provisional applicationNo. 61/978,646, filed Apr. 11, 2014, the entire respective disclosuresof which are incorporated herein by reference.

GOVERNMENT RIGHTS

This invention was made with government support under grants GM073836and EB005172 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

BACKGROUND

Field of the Invention

The present invention generally relates to copper-catalyzedradiofluorination of iodonium salts, to iodonium salts and compoundsobtained by copper-catalyzed radiofluorination of iodonium salts, and todiagnostic and therapeutic methods involving such compounds.

Brief Description of Related Technology

Positron emission tomography (PET) is a powerful and minimally invasivemedical imaging technique that provides kinetic physiochemicalinformation. The most commonly used radioisotope for PET is ¹⁸F, whichoffers the advantages of high resolution imaging (ca. 2.5 mm in tissue),a relatively long lifetime (t_(1/2)=110 min), and minimal perturbationof radioligand binding. Despite these advantages, the development ofnovel ¹⁸F radiotracers is currently impeded by a paucity of general andeffective radiofluorination methods. There are currently few robustsynthetic procedures for the incorporation of ¹⁸F into organic moleculeswith sufficient speed, selectivity, yield, radiochemical purity, andreproducibility to provide clinical imaging materials. Direct methodsfor the late stage nucleophilic [¹⁸F]fluorination of electron-richaromatic substrates remains an especially long-standing challenge in thePET community. A target of particular interest in this regard is6-[¹⁸F]fluoro-_(L)-DOPA (6-[¹⁸F]fluoro-_(L)-3,4-dihydroxyphenylalanine),which serves as a valuable diagnostic for probing the regionaldistribution of dopamine in the human brain. While there has been muchactivity in the radiofluorination community aimed at accessing6-[¹⁸F]fluoro-_(L)-DOPA, current methods suffer from drawbacks(including low specific activity, multi-step procedures, chiralseparations, and/or poor yield) that limit routine production of thismaterial.

The majority of radiofluorination methods for electron rich aryl ringsutilize electrophilic fluorinating reagents derived from [¹⁸F]F₂.However, [¹⁸F]F₂ production typically requires ¹⁹F₂ as a carrier gas,which leads to low specific activity (SA) radiotracers (typically <1.0Ci/mmol) and requires specialized facilities. The development of [¹⁸F]KFproduction from [¹⁸O]water has provided the means to synthesize high SAradiotracers (>1,000 Ci/mmol) through nucleophilic substitution(typically S_(N)2 or S_(N)Ar). However, the use of [¹⁸F]KF is generallylimited to the formation of primary sp³-C—F bonds or sp²-C—F bonds onactivated electron deficient aromatics.

Two main strategies have been used to address these limitations. Thefirst involves radiofluorination of powerful electrophiles such asdiaryliodonium salts. Diaryliodonium salts bearing the 2-thienyl grouphave been shown to react with [¹⁸F]KF at elevated temperatures (often≥150° C.) to afford [¹⁸F]fluoroarenes (Scheme 1). In these systems, the2-thienyl group directs radiofluorination to the other aromatic ligandon iodine, with moderate to good selectivity. However, the[(thienyl)(aryl)I⁺] starting materials are often challenging to prepare,suffer from low stability, and have a limited shelf-life. Furthermore,with electron neutral or rich substrates, these transformationsfrequently require high temperatures, exhibit modest regioselectivity,demonstrate limited functional group tolerance, and provide lowradiochemical yields. As such, it has proven challenging to accessimportant radiotracers, most notably 6-[¹⁸F]fluoro-_(L)-DOPAderivatives, using this method.

A second strategy applies transition metal catalysts and/or reagents toachieve nucleophilic radiofluorination. Transition metal catalysisoffers opportunities for accelerating radiofluorination reaction ratesas well as enhancing selectivity and reactivity. For instance, progresshas been made in nucleophilic radiofluorination using Pd (Lee, E.,Science 334:639 (2011); Kamlet, A. S., PLoS One 8:e59187 (2013)) and Ni(Lee, E., J. Am. Chem. Soc. 134:17456 (2012)) complexes. However, therequirement for the multistep synthesis of organometallic reagents underinert atmospheres has thus far limited adoption of these methods bynon-experts.

Fluorination reactions disclosed in WO 2010/048170 also suffer fromvarious deficiencies.

The present invention provides a general, mild, high-yielding, anduser-friendly procedure for the radiofluorination of diverse aromaticsubstrates by merging transition metal catalysis with the fluorinationof diaryliodonium salts.

SUMMARY

The present invention is directed to methods for radiofluorinatingorganic compounds, to compounds obtained by such methods, to diagnosticand therapeutic methods involving such compounds, and to iodonium saltsuseful for obtaining radiolabeled organic compounds.

In one embodiment, the present invention provides a method forradiofluorinating organic compounds by reacting a diaryliodonium saltwith an ¹⁸F source in the presence of a copper source. Thediaryliodonium salt has a Formula (1):

wherein Ar¹ and Ar² independently are aryl groups; and X⁻ is an anion.The reacting is carried out under conditions sufficient to form aradiolabeled aryl fluoride of Formula (2):

In a further embodiment, the invention provides a method of diagnosingor treating a disease or condition comprising administering aradiolabeled aryl fluoride as described herein to a subject in needthereof.

Another embodiment of the present invention is a diaryliodonium salt ofFormula (5)

wherein X⁻ is an anion; each R⁴ is independently selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, t-butyl, aryl, and benzyl; n is selected from the groupconsisting of 1, 2, 3, 4, and 5; each P¹ is independently selected fromalcohol protecting groups; m is selected from the group consisting of 0,1, and 2; P² is H; and P³ is an amino protecting group; or P² and P³,taken together with the nitrogen atom to which they are attached, form acyclic amino protecting group; Y is selected from the group consistingof O, S, and NP⁵; P⁴ is a protecting group; P⁵ is H; or P⁴ and P⁵, takentogether with the nitrogen atom to which they are attached, form acyclic amino protecting group; or P² and P⁴, taken together with theatoms to which they are attached, form a cyclic protecting group.

These and other embodiments and features of the present invention willbecome apparent from the following detailed description of the preferredembodiments.

DETAILED DESCRIPTION

Disclosed herein are methods for radiolabeling aryl fluorides. Themethods comprise reacting a diaryliodonium salt with an ¹⁸F source inthe presence of a copper source. The reacting is carried out underconditions sufficient to convert the diaryliodonium salt to an arylfluoride to provide the radiolabeled aryl fluoride. The disclosedmethods provide radiolabeled compounds having a high specific activityand utilize starting materials including electron rich, electronneutral, and electron deficient arene substrates. The disclosed methodsprovide various radiolabeled compounds including, but not limited to,clinically relevant compounds such as protected4-[¹⁸F]fluoro-_(L)-phenylalanine, protected 3-[¹⁸F]fluorotyrosine, andprotected 6-[¹⁸F]fluoro-_(L)-DOPA.

The use of the terms “a,” “an,” “the,” and similar referents in thecontext of describing the invention (especially in the context of theclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated. Recitation of ranges of values herein merelyare intended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended to better illustrate the invention and is not a limitation onthe scope of the invention unless otherwise claimed. No language in thespecification should be construed as indicating any non-claimed elementas essential to the practice of the invention.

As used herein, the term “alkyl” refers to straight chained and branchedhydrocarbon groups, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. The term C_(m-n)means the alkyl group has “m” to “n” carbon atoms. The term “alkylene”refers to an alkyl group having a substituent. An alkyl, e.g., methyl,or alkylene, e.g., —CH₂—, group can be substituted with one or more, andtypically one to three, of independently selected halo, trifluoromethyl,trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, or aminogroups, for example.

As used herein, the term “halo” refers to fluoro, chloro, bromo, andiodo.

The term “hydroxy” is defined as —OH.

The term “alkoxy” is defined as —OR, wherein R is alkyl.

The term “amino” is defined as —NH₂, and the term “alkylamino” isdefined as —NR₂, wherein at least one R is alkyl and the second R isalkyl or hydrogen.

The term “carbamoyl” is defined as —C(═O)NR₂.

The term “carboxy” is defined as —C(═O)OH or a salt thereof.

The term “nitro” is defined as —NO₂.

The term “cyano” is defined as —CN.

The term “trifluoromethyl” is defined as —CF₃.

The term “trifluoromethoxy” is defined as —OCF₃.

As used herein, the term “aryl” refers to a monocyclic or polycyclicaromatic group, preferably a monocyclic or bicyclic aromatic group.Examples of aryl groups include, but are not limited to, phenyl,naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl,and terphenyl. Aryl also refers to bicyclic and tricyclic carbon rings,where one ring is aromatic and the others are saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). Unless otherwise indicated,an aryl group can be unsubstituted or substituted with one or more, andin particular one to four, groups independently selected from, forexample, halo, alkyl, alkenyl, —OCF₃, —NO₂, —CN, —NC, —OH, alkoxy,amino, alkylamino, —CO₂H, —CO₂alkyl, —OCOalkyl, aryl, and heteroaryl.

As used herein, the term “benzyl” refers to —CH₂— phenyl. Unlessotherwise indicated, a benzyl group can be unsubstituted or substitutedwith one or more, and in particular one to four, groups independentlyselected from, for example, halo, alkyl, alkenyl, —OCF₃, —NO₂, —CN, —NC,—OH, alkoxy, amino, alkylamino, —CO₂H, —CO₂alkyl, —OCOalkyl, aryl, andheteroaryl.

As used herein, the term “heterocyclic” refers to a heteroaryl andheterocycloalkyl ring systems.

As used herein, the term “heteroaryl” refers to a monocyclic or bicyclicring system containing one or two aromatic rings and containing at leastone nitrogen, oxygen, or sulfur atom in an aromatic ring. Each ring of aheteroaryl group can contain one or two O atoms, one or two S atoms,and/or one to four N atoms, provided that the total number ofheteroatoms in each ring is four or less and each ring contains at leastone carbon atom. In certain embodiments, the heteroaryl group has from 5to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclicheteroaryl groups include, but are not limited to, furanyl, imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl,thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclicheteroaryl groups include, but are not limited to, benzofuranyl,benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl,benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl,benzoxazolyl, fluoropyridyl, imidazopyridinyl, imidazothiazolyl,indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl,isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,thiadiazolopyrimidyl, and thienopyridyl. Unless otherwise indicated, aheteroaryl group can be unsubstituted or substituted with one or more,and in particular one to four, substituents selected from, for example,halo, alkyl, alkenyl, —OCF₃, —NO₂, —CN, —NC, —OH, alkoxy, amino,alkylamino, —CO₂H, —CO₂alkyl, —OCOalkyl, aryl, and heteroaryl.

As used herein, the term “cycloalkyl” means a monocyclic or bicyclic,saturated or partially unsaturated, ring system containing three toeight carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted with oneor more, and typically one to three, of independently selected halo,trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano,alkylamino, or amino groups, for example.

As used herein, the term “heterocycloalkyl” means a monocyclic or abicyclic, saturated or partially unsaturated, ring system containing 4to 12 total atoms, of which one to five of the atoms are independentlyselected from nitrogen, oxygen, and sulfur and the remaining atoms arecarbon. Nonlimiting examples of heterocycloalkyl groups are azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, dihydropyrrolyl, morpholinyl,thiomorpholinyl, dihydropyridinyl, oxacycloheptyl, dioxacycloheptyl,thiacycloheptyl, diazacycloheptyl, each optionally substituted with oneor more, and typically one to three, of independently selected halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C₂₋₇alkenyl, C₂₋₇ alkynyl, or the like on an atom of the ring.

In one aspect, a method is provided for preparing a radiolabeled arylfluoride of Formula (2) comprising reacting a diaryliodonium salt ofFormula (1):

with an ¹⁸F source in the presence of a copper source under conditionssufficient to form the radiolabeled aryl fluoride of Formula (2):

wherein Ar¹ and Ar² independently are aryl groups; and X⁻ is an anion.

In some embodiments, Ar¹ is has a structure of Formula (3):

wherein R¹, R², and R³ are independently selected from the groupconsisting of H, C₁₋₄alkyl, OR^(a), NR^(a)R^(b), halo,—NR^(a)C(═O)R^(b), —C(═O)NR^(a)R^(b), —OC(═O)R^(a), —C(═O)OR^(a),—C(═O)R^(a), aryl, benzyl, and

orR² and R³, taken together with the carbon atoms to which they areattached, form a 4- to 8-membered ring; R^(a) is selected from the groupconsisting of H, C₁₋₄alkyl, aryl, and benzyl; and R^(b) is selected fromthe group consisting of H, C₁₋₄alkyl, aryl, benzyl, —O—C₁₋₄alkyl,—O-aryl, and —O-benzyl; with the proviso that at least one of R¹, R²,and R³ is other than H. In some embodiments, R² and R³, taken togetherwith the carbon atoms to which they are attached, form a substituted 4-to 8-membered ring.

Ar¹ groups include, but are not limited to, the following:

In some embodiments, Ar² has a structure of Formula (4):

wherein each R⁴ is independently selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, aryl, and benzyl; and n is selected from the group consistingof 1, 2, 3, 4, and 5.

In some embodiments, Ar² has the following structure:

wherein each R⁴ is independently selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, aryl, and benzyl.

Ar² groups include, but are not limited to, the following:

Diaryliodonium ions (i.e., ions of formula Ar¹—I⁺—Ar²) include, but arenot limited to, the following:

In various embodiments, the iodonium salt comprises a counteranion(i.e., X⁻) including, but not limited to, halides (e.g., fluoride,chloride, bromide, iodide), trifluoromethanesulfonate (triflate, ⁻OTf),toluene sulfonate (tosylate, ⁻OTs), tetrafluoroborate,hexafluorophosphate, methanesulfonate (mesylate),hexafluoropropanesulfonate, nonafluorobutanesulfonate (nonaflate),nitrophenyl sulfonate (nosylate), bromophenyl sulfonate (brosylate),perfluoroalkyl sulfonate (e.g., perfluoro C₂₋₁₀ alkyl sulfonate),tetraphenylborate, trifluoroacetate, perfluoroalkylcarboxylate,perchlorate, hexafluorostibate, hexachlorostibate, acetate, andbenzoate.

In various embodiments, the copper source includes, but is not limitedto, copper(II) trifluoromethanesulfonate (Cu(OTf)₂), copper(II)carbonate basic (CuCO₃.Cu(OH)₂), copper(I) trifluoromethanesulfonatetoluene complex (CuOTf.toluene), tetrakisacetonitrile copper(I) triflate((CH₃CN)₄CuOTf), ammonium tetrachlorocuprate(II), copperbenzene-1,3,5-tricarboxylate,bis(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)copper(I)tetrafluoroborate,bis[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]copper(I)tetrafluoroborate, bis(ethylenediamine)copper(II) hydroxide,(R,R)-(−)-N,N′-bis(3-hydroxylsalicylidene)-1,2-cyclohexanediaminocopper(II)samariumisopropoxide, bis[(tetrabutylammonium iodide)copper(I) iodide],[bis(trimethylsilyl)acetylene](hexafluoroacetylacetonato)copper(I),bromotris(triphenylphosphine)copper(I), 5-chlorobenzo[b]phosphindole,chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I),copper(I) acetate, copper(II) acetate 1,2-bis(diphenylphosphino)ethane,copper(II) acetylacetonate, copper(I) bromide, copper(I) bromidedimethyl sulfide complex, copper(II) tert-butylacetoacetate, copper(II)carbonate, copper(I) chloride, copper(II) chloride, copper(I)chloride-bis(lithium chloride) complex, copper(I) cyanide di(lithiumchloride) complex, copper(II) 3,5-diisopropylsalicylate, copper (I)diphenylphosphinate, copper(II) ethylacetoacetate, copper(II)2-ethylhexanoate, copper formate, copper hydride, copper(I) iodide,copper iodide dimethyl sulfide complex, copper(I) iodidetrimethylphosphite complex, copper(I) 3-methylsalicylate, copper(II)nitrate, copper(I) oxide, copper oxychloride, copper(II) sulfate,copper(II) tartrate, copper(II) tetrafluoroborate, copper(I)thiophene-2-carboxylate, copper(I) thiophenolate,di-μ-hydroxo-bis[(N,N,N′,N′-tetramethylethylenediamine)copper(II)]chloride, copper(I) trifluoromethanesulfonate benzene complex, cupriccarbonate, {Cuprous2-[(2-diphenylphosphino)benzylideneamino]-3,3-dimethylbutyrate,triflatesodiumtriflate} complex, (1,4-diazabicyclo[2.2.2]octane)copper(I) chloridecomplex, dichloro(1,10-phenanthroline)copper(II), dilithiumtetrachlorocuprate(II),hydro[(4R)-[4,4′-bi-1,3-benzodioxole]-5,5′-diylbis[bis[3,5-bis(1,1-dimethylethyl)-4-methoxyphenyl]phosphine-P]]copper(I),(ethylcyclopentadienyl)(triphenylphosphine)copper(I),fluorotris(triphenylphosphine)copper(I), iodo(triethylphosphite)copper(I), mesitylcopper(I),(1,10-phenanthroline)bis(triphenylphosphine)copper(I) nitratedichloromethane adduct, phthalocyanine green,tetrakis(acetonitrile)copper(I) hexafluorophosphate,tetrakis(acetonitrile)copper(I) tetrafluoroborate, andtetrakis(pyridine)copper(II) triflate.

In various embodiments, the ¹⁸F source includes, but is not limited to,¹⁸F-labeled alkali metal fluorides and alkaline earth metal fluorides(e.g., ¹⁸F lithium fluoride, ¹⁸F sodium fluoride, ¹⁸F potassiumfluoride, ¹⁸F rubidium fluoride, ¹⁸F cesium fluoride, ¹⁸F berylliumfluoride, ¹⁸F magnesium fluoride, ¹⁸F calcium fluoride), ¹⁸F-labeledammonium fluorides (e.g., ¹⁸F-labeled tetraalkylammonium fluorides suchas ¹⁸F tetramethylammonium fluoride, ¹⁸F tetraethylammonium fluoride,¹⁸F tetrapropylammonium fluoride, and ¹⁸F tetrabutylammonium fluoride),and complexes thereof with complexing compounds such as crown ethers(e.g., complexes with 12-crown-4, 15-crown-5, 18-crown-6,dibenzo-18-crown-6, and diaza-18-crown-6), for example, ¹⁸F potassiumfluoride.18-crown-6 complex.

The ¹⁸F fluorination reaction can be carried out in various solvents.Suitable solvents include, but are not limited to, polar proticsolvents, polar aprotic solvents, nonpolar solvents, alcohols, esters,ethers, amides, glycols, glycol ethers, aliphatic and aromatichydrocarbons, chlorinated solvents, C₁₋₆alcohols (e.g., methanol,ethanol, propyl alcohol, and butyl alcohol, including isomers thereof),monoC₁₋₄alkyl ethers of ethylene glycol and propylene glycol, acetone,methyl ethyl ketone, isophorone, dichloromethane, chloroform, ethylacetate, 2-methoxyethanol, dimethylformamide (DMF), dimethyl sulfoxide(DMSO), tetrahydrofuran (THF), acetonitrile, kerosene, mineral spirits,xylene, toluene, and mixtures thereof.

The ¹⁸F fluorination reaction can be carried out at various molar ratiosof copper source to diaryliodonium salt. Suitable molar ratios of coppersource to diaryliodonium salt include, but are not limited to, about1:20 to about 5:1, about 1:10 to about 3:1, about 1:5 to about 2:1,and/or about 1:2 to 1:1.

The ¹⁸F fluorination reaction can be carried out at various loadinglevels of the diaryliodonium salt. Suitable loading levels of thediaryliodonium salt include, but are not limited to, about 1 μmol orgreater, about 2 μmol or greater, about 3 μmol or greater, about 4 μmolor greater, about 5 μmol or greater, about 6 μmol or greater, about 10μmol or greater, about 20 μmol or greater, about 30 μmol or greater,about 50 μmol or greater, about 1 μmol to about 100 μmol, about 2 μmolto about 50 μmol, about 3 μmol to about 30 μmol, and/or about 5 μmol toabout 20 μmol.

The ¹⁸F fluorination reaction can be carried out at varioustemperatures. Suitable reaction temperatures include, but are notlimited to, a temperature of about 0° C. to about 150° C., such as about20° C. to about 140° C., about 40° C. to about 130° C., about 50° C. toabout 120° C., about 60° C. to about 110° C., about 70° C. to about 100°C., and/or about 80° C. to about 90° C.

The ¹⁸F fluorination reaction can be carried out for various lengths oftime. Suitable reaction times include, but are not limited to, areaction time of about 1 minute or greater, about 5 minutes or greater,about 10 minutes or greater, about 15 minutes or greater, about 20minutes or greater, about 30 minutes or greater, and/or about 45 minutesor greater.

¹⁸F-labeled aryl fluorides of Formula (2) prepared according to themethods disclosed herein are obtained in high radiochemical yield (RCY).For example, the products of the methods disclosed herein are obtainedin a radiochemical yield of about 5% or greater, about 10% or greater,about 20% or greater, about 30% or greater, about 40% or greater, about50% or greater, about 60% or greater, and/or about 70% or greater.

In various embodiments, the radiolabeled aryl fluoride of Formula (2) isisolated. Suitable methods of isolating the radiolabeled aryl fluorideof Formula (2) include, but are not limited to, extraction,chromatography, and crystallization.

In one aspect, the disclosure provides a method of diagnosing ortreating a disease or condition comprising administering a radiolabeledaryl fluoride as described herein to a subject in need thereof.4-[¹⁸F]fluoro-L-phenylalanine, for example, can be used as a probe ofpancreatic and cerebral protein synthesis. Advantageously, the methodsdescribed herein provide radiofluorinated compounds such as4-[¹⁸F]fluoro-L-phenylalanine in high specific activity andradiochemical yield.

Also provided are methods for preparing aryl fluorides comprisingreacting a diaryliodonium salt with an ¹⁹F source in the presence of acopper source, wherein the reacting is carried out under conditionssufficient to convert the diaryliodonium salt to an aryl fluoride toprovide the aryl fluoride. (Ichiishi, N., Org. Lett., 15:5134 (2013)).Suitable diaryliodonium salts, copper sources, and conditions aredescribed herein. Suitable ¹⁹F sources include, but are not limited to,alkali metal fluorides and alkaline earth metal fluorides (e.g., lithiumfluoride, sodium fluoride, potassium fluoride, rubidium fluoride, cesiumfluoride, beryllium fluoride, magnesium fluoride, calcium fluoride),ammonium fluorides (e.g., tetraalkylammonium fluorides such astetramethylammonium fluoride, tetraethylammonium fluoride,tetrapropylammonium fluoride, and tetrabutylammonium fluoride), andcomplexes thereof with complexing compounds such as crown ethers (e.g.,complexes with 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6,and diaza-18-crown-6), for example, potassium fluoride.18-crown-6complex.

In another aspect, the disclosure is directed to a compound of Formula(5):

wherein X⁻ is an anion; each R⁴ is independently selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, t-butyl, aryl, and benzyl; n is selected from the groupconsisting of 1, 2, 3, 4, and 5; each P¹ is independently selected fromalcohol protecting groups; m is selected from the group consisting of 0,1, and 2; P² is H; P³ is an amino protecting group; or P² and P³, takentogether with the nitrogen atom to which they are attached, form acyclic amino protecting group; Y is selected from the group consistingof O, S, and NP⁵; P⁴ is a protecting group; P⁵ is H; or P⁴ and P⁵, takentogether with the nitrogen atom to which they are attached, form acyclic amino protecting group; or P² and P⁴, taken together with theatoms to which they are attached, form a cyclic protecting group.Suitable anions include, but are not limited to, fluoride, chloride,bromide, iodide, trifluoromethanesulfonate, toluene sulfonate,tetrafluoroborate, hexafluorophosphate, methanesulfonate,hexafluoropropanesulfonate, nonafluorobutanesulfonate, nitrophenylsulfonate, bromophenyl sulfonate, perfluoroalkyl sulfonate,tetraphenylborate, trifluoroacetate, perfluoroalkylcarboxylate,perchlorate, hexafluorostibate, hexachlorostibate, acetate, andbenzoate.

In some embodiments, the compound of Formula (5) has a structure ofFormula (6)

In some embodiments, the compound of Formula (5) has a structure ofFormula (7)

In some embodiments, the compound of Formula (5) has a structure ofFormula (8)

In some embodiments, the compound of Formula (5) has a structure of (9)

Various protecting groups can be used. Suitable protecting groupsinclude, but are not limited to, protecting groups of formula R^(a),—C(═O)R^(a), and —C(═O)OR^(a), wherein R^(a) is C₁₋₄alkyl, aryl, andbenzyl. For example, suitable protecting groups include methyl, acetyl,and pivaloyl. In some embodiments, P¹, P³, and P⁴ are independentlyselected from the group consisting of R^(a), —C(═O)R^(a), and—C(═O)OR^(a); wherein R^(a) is selected from the group consisting ofC₁₋₄alkyl, aryl, and benzyl.

In some embodiments, P² and P³, taken together with the nitrogen atom towhich they are attached, form a cyclic amino protecting group having thestructure:

In some embodiments, P² and P⁴, taken together with the atoms to whichthey are attached, form a cyclic protecting group having the structure:

wherein R^(a) is selected from the group consisting of H, C₁₋₄alkyl,aryl, and benzyl. For example, P² and P⁴, taken together with the atomsto which they are attached, form a cyclic protecting group having thestructure:

and/or the structure:

EXAMPLES Example 1—Synthesis of [¹⁸F]KF.18-Crown-6 Complex

Potassium [¹⁸F]fluoride was prepared using a TRACERLab FXFN automatedradiochemistry synthesis module (General Electric, GE). All loadingoperations were conducted under ambient atmosphere. Argon was used as apressurizing gas during automated sample transfers. [¹⁸F]Fluoride wasproduced via the ¹⁸O(p,n)¹⁸F nuclear reaction using a GE PETTracecyclotron (40 μA beam for 2 min generated ca. 150 mCi of [¹⁸F]fluoride).The [¹⁸F]fluoride was delivered to the synthesis module in a 1.5 mLbolus of [¹⁸O]water and trapped on a QMA-light Sep-Pak to remove[¹⁸O]water. [¹⁸F]Fluoride was eluted into the reaction vessel usingaqueous potassium carbonate (3.5 mg in 0.5 mL of water). A solution of18-crown-6 (15 mg in 1 mL of acetonitrile) was added to the reactionvessel, and the resulting solution was dried by azeotropic distillationto give dry [¹⁸F]KF.18-crown-6. Evaporation was achieved by heating thereaction vessel to 100° C. and drawing vacuum for 4 min. After thistime, the reaction vessel was subjected to an argon stream andsimultaneous vacuum draw for an additional 4 min. Finally,N,N-dimethylformamide (8 mL) was added to the dried reagent, and theresulting solution was transferred to a sterile vial for subsequent usein reactions (approx. 30 mCi of prepared ¹⁸F reagent was transferred).

Example 2—General Procedure for Manual Synthesis of ¹⁸F-LabeledCompounds

On the bench top, solid [Mes-I—Ar]X (6 μmol) was weighed into a 4 mLamber glass vial containing a stir bar and was then dissolved in DMF(350 μL). A stock solution of tetrakis(acetonitrile)copper(I) triflate(CuOTf) was prepared (14.3 mg in 1 mL of anhydrous DMF, 0.04 M), andaliquots of this solution were used for several reactions. A 150 μLaliquot of CuOTf solution (6 μmol) was added to the vial containing[Mes-I—Ar]X. The reaction vial was sealed under an atmosphere of ambientair with a PTFE/Silicone septum cap, and then the solution wasthoroughly mixed (vortex shaker, Barnstead® Thermolyne Type 16700). Viaa syringe, a 250 μL aliquot of [¹⁸F]KF.18-crown-6 complex (typically300-700 μCi, prepared as described in Example 1) was added to thereaction vial. The vial was then heated in an aluminum block withstirring at 85° C. for 20 min. After 20 min, the reaction was allowed tocool to room temperature. A 100 μL aliquot was withdrawn from the vialand added to 400 or 900 μL of CH₂Cl₂ in a 4 mL vial (choice of volume ofCH₂Cl₂ was dependent on activity). The CH₂Cl₂ mixture was shaken by handand then used for radio-TLC analysis to obtain radiochemical yields(RCY). In addition, a 100 μL aliquot of the reaction solution was usedfor radio-HPLC analysis by diluting the sample into 50/50 MeCN/H₂O (300μL total volume).

Example 3—General Procedure for Automated Synthesis of ¹⁸F-LabeledCompounds

The production-scale synthesis of radiolabeled arenes was conductedusing a TRACERLab FXFN automated radiochemistry synthesis module(General Electric, GE). The synthesis module was pre-charged with asolution of the [Mes-I—Ar]X precursor (18 μmol) and tetrakisacetonitrilecopper(I) triflate (8.0 mg, 20 μmol) in DMF (0.75 mL) to be added froman automated port prior to ¹⁸F delivery. [¹⁸F]Fluoride was produced viathe ¹⁸O(p,n)¹⁸F nuclear reaction using a GE PETTrace cyclotron (40 μAbeam for 30 min generated 1,500 mCi of [¹⁸F]fluoride). The [¹⁸F]fluoridewas delivered to the synthesis module (in a 1.5 mL bolus of [¹8O]water)and trapped on a QMA-light Sep-Pak to remove [¹⁸O]water. [¹⁸F]Fluoridewas eluted into the reaction vessel using aqueous potassium carbonate(3.0 mg in 0.5 mL of water). A solution of 18-crown-6 (5 mg in 1 mL ofacetonitrile) was added to the reaction vessel, and the resultingsolution was dried by azeotropic distillation to give dry[¹⁸F]KF.18-crown-6. Evaporation was achieved by heating the reactionvessel to 100° C. and drawing vacuum for 4 min. After this time, thereaction vessel was subjected to an argon stream and simultaneous vacuumdraw for an additional 4 min. The reaction vessel was cooled to 50° C.,DMF (0.75 mL) was added, and the resulting mixture was stirred for 1min. A preloaded solution of iodonium salt and copper was added to thereaction vessel, and the vessel was sealed, heated to 85° C., and heldat that temperature for 20 min. The reaction vessel was then cooled to50° C., and DMF (8.5 mL) was added. The additional DMF was used toreduce hand exposure during sample manipulations and analysis. Theresulting solution (10 mL) was transferred to a sterile vial foranalysis (radio-TLC and radio-HPLC).

Example 4—Manual Synthesis of 4-[¹⁸F]Fluoroanisole

4-[¹⁸F]Fluoroanisole was prepared by the general procedure for manualsynthesis of ¹⁸F-labeled compounds described in Example 2, except thatthe copper catalyst, diaryliodonium salt, and reaction conditions wereas shown in Table 1.

TABLE 1 Synthesis of 4-[¹⁸F]Fluoroanisole

RCY* of 4- Example [Cu] X [¹⁸F]Fluoranisole 4a^(†) Cu(OTF)₂ BF₄ 36 ± 19%(n = 15) 4b^(†) CuCO₃•Cu(OH)₂ BF₄ 10 ± 6% (n = 3) 4c^(†) CuOTf•tolueneBF₄ 43 ± 15% (n = 3) 4d^(†) (CH₃CN)₄CuOTf BF₄ 70 ± 11% (n = 11) 4e^(†)none BF₄ <1% 4f^(‡) (CH₃CN)₄CuOTf BF₄ 79 ± 8% (n = 38) 4g^(‡)(CH₃CN)₄CuOTf PF₆ 53 ± 7% (n = 3) 4h^(‡) (CH₃CN)₄CuOTf OTs 45 ± 26% (n =3) 4i^(‡) (CH₃CN)₄CuOTf OTf <1% 4j^(‡) (CH₃CN)₄CuOTf Br <1%*Radiochemical Yield (RCY) was determined by radio-TLC (average of nruns). The identity of 4-[¹⁸F]fluoroanisole was confirmed by HPLC.^(†)Conditions: [4-OMePh-I-Mes]X (6 μmol), [Cu] (3 μmol),[¹⁸F]KF•18-crown-6 in DMF (250 μL, 300-700 μCi), total volume 750 μL.^(‡)Conditions: [4-OMePh-I-Mes]X (6 μmol), [Cu] (6 μmol),[¹⁸F]KF•18-crown-6 in DMF (250 μL, 300-700 μCi), total volume 750 μL.

As demonstrated in Table 1, 6 μmol [4-OMePh-I-Mes]BF₄ was converted to4-[¹⁸F]fluoroanisole in 36% radiochemical yield (RCY) in 20 min at 85°C. with 3 μmol Cu(OTf)₂ as the catalyst (1:2 ratio of copper catalyst todiaryliodonium salt), DMF as the solvent, and [¹⁸F]KF-18-crown-6 as thefluoride source (Example 4a). High selectivity was observed for4-[¹⁸F]fluoroanisole, with <1% of [¹⁸F]fluoromesitylene detected byradio-TLC or radio-HPLC. The reaction demonstrated reproducibility of±19% yield over 15 runs.

Also as demonstrated in Table 1, 6 μmol [4-OMePh-I-Mes]BF₄ was convertedto 4-[¹⁸F]fluoroanisole in 70% radiochemical yield (RCY) in 20 min at85° C. with 3 μmol (CH₃CN)₄CuOTf as the catalyst (1:2 ratio of coppercatalyst to diaryliodonium salt), DMF as the solvent, and[¹⁸F]KF-18-crown-6 as the fluoride source (Example 4d). The reactiondemonstrated reproducibility of ±11% yield over 11 runs. Additionally asdemonstrated in Table 1, 6 μmol [4-OMePh-I-Mes]BF₄ was converted to4-[¹⁸F]fluoroanisole in 79% radiochemical yield (RCY) in 20 min at 85°C. with 6 μmol (CH₃CN)₄CuOTf as the catalyst (1:1 ratio of coppercatalyst to diaryliodonium salt), DMF as the solvent, and[¹⁸F]KF-18-crown-6 as the fluoride source (Example 40. The reactiondemonstrated reproducibility of ±8% yield over 38 runs.

Example 4e demonstrated that in the absence of copper catalyst, nodetectable 4-[¹⁸F]fluoroanisole was obtained and only 6% RCY[¹⁸F]fluoromesitylene was obtained.

Example 5—Manual Synthesis of 4-[¹⁸F]Fluoroanisole

4-[¹⁸F]Fluoroanisole was prepared by the general procedure for manualsynthesis of ¹⁸F-labeled compounds described in Example 2, except thatthe molar ratio of copper catalyst and diaryliodonium salt were as shownin Table 2.

TABLE 2 Molar Ratio of (CH₃CN)₄CuOTf to[4-OMePh-I-Mes]BF₄

Example* [Cu]: Ar₂I⁺ % RCY 5a 0:1 <1% (n = 11) 5b 1:5 55 ± 5% (n = 3) 5c1:2 70 ± 11% (n = 11) 5d 1:1 79 ± 8% (n = 28) 5e 2:1 45 ± 9% (n = 3)*Conditions: [4-OMePh-I-Mes]BF₄ (6 μmol, (CH₃CN)₄CuOTf (varies),[¹⁸F]KF•18-crown-6 in DMF (250 μL, 300-700 μCi), total volume 750 μL.

As demonstrated in Table 2, 6 μmol [4-OMePh-I-Mes]BF₄ was converted to4-[¹⁸F]fluoroanisole in 79% radiochemical yield (RCY) in 20 min at 85°C. with 6 μmol (CH₃CN)₄CuOTf as the catalyst (1:1 ratio of coppercatalyst to diaryliodonium salt), DMF as the solvent, and[¹⁸F]KF-18-crown-6 as the fluoride source (Example 5d). The reactiondemonstrated reproducibility of ±8% yield over 28 runs.

Example 6—Manual Synthesis of 4-[¹⁸F]Fluoroanisole

4-[¹⁸F]Fluoroanisole was prepared by the general procedure for manualsynthesis of ¹⁸F-labeled compounds described in Example 2, except thatthe loading of copper catalyst and diaryliodonium salt were as shown inTable 3.

TABLE 3 Loading of [4-OMePh-I-Mes]BF₄ and (CH₃CN)₄CuOTf

μmol [4-OMePh-I-Mes]BF₄ and Example* (CH₃CN)₄CuOTf % RCY 6a  6 79 ± 8%(n = 37) 6b  3 68 ± 4% (n = 3) 6c 11 72 ± 3% (n = 3) 6d 23 48 ± 11% (n =3) *Conditions: [4-OMePh-I-Mes]BF₄ (3-23 μmol), (CH₃CN)₄CuOTf (3-23μmol, [¹⁸F]KF•18-crown-6 in DMF (250 μL, 300-700 μCi), total volume 750μL.

As demonstrated in Table 3, 6 μmol [4-OMePh-I-Mes]BF₄ was converted to4-[¹⁸F]fluoroanisole in 79% radiochemical yield (RCY) in 20 min at 85°C. with 6 μmol (CH₃CN)₄CuOTf as the catalyst (1:1 ratio of coppercatalyst to diaryliodonium salt), DMF as the solvent, and[¹⁸F]KF-18-crown-6 as the fluoride source (Example 6a). The reactiondemonstrated reproducibility of ±8% yield over 37 runs.

Example 7—Manual Synthesis of 4-[¹⁸F]Fluoroanisole

4-[¹⁸F]Fluoroanisole was prepared by the general procedure for manualsynthesis of ¹⁸F-labeled compounds described in Example 2, except thatthe temperature was as shown in Table 4.

TABLE 4 Reaction Temperature

Example* Temperature (° C.) % RCY (n = 3) 7a  60 39 ± 8% 7b  85 76 ± 3%7c 100 43 ± 16% 7d 115 52 ± 12% *Conditions: [4-OMePh-I-Mes]BF₄ (6 μmol,(CH₃CN)₄CuOTf (6 μmol, [¹⁸F]KF•18-crown-6 in DMF (250 μL, 300-700 μCi),total volume 750 μL.

As demonstrated in Table 4, 6 μmol [4-OMePh-I-Mes]BF₄ was converted to4-[¹⁸F]fluoroanisole in 76% radiochemical yield (RCY) in 20 min at 85°C. with 6 μmol (CH₃CN)₄CuOTf as the catalyst (1:1 ratio of coppercatalyst to diaryliodonium salt), DMF as the solvent, and[¹⁸F]KF-18-crown-6 as the fluoride source (Example 7b). The reactiondemonstrated reproducibility of ±3% yield over 3 runs. As temperaturewas increased, additional peaks were observed in the UV trace of theHPLC analysis.

Example 8—Manual Synthesis of 4-[¹⁸F]Fluoroanisole

4-[¹⁸F]Fluoroanisole was prepared by the general procedure for manualsynthesis of ¹⁸F-labeled compounds described in Example 2, except thatthe reaction time was as shown in Table 5.

TABLE 5 Reaction Time

Example* Time (min) % RCY (n = 2) 8a  5 33 ± 2% 8b 10 55 ± 10% 8c 15 52± 35% 8d 20 69 ± 1% 8e 30 65 ± 5% 8f 45 64 ± 8% *Conditions:[4-OMePh-I-Mes]BF₄ (6 μmol, (CH₃CN)₄CuOTf (6 μmol), [¹⁸F]KF•18-crown-6in DMF (250 μL, 300-700 μCi), total volume 750 μL.

As demonstrated in Table 5, 6 μmol [4-OMePh-I-Mes]BF₄ was converted to4-[¹⁸F]fluoroanisole in 69% radiochemical yield (RCY) in 20 min at 85°C. with 6 μmol (CH₃CN)₄CuOTf as the catalyst (1:1 ratio of coppercatalyst to diaryliodonium salt), DMF as the solvent, and[¹⁸F]KF-18-crown-6 as the fluoride source (Example 8d). The reactiondemonstrated reproducibility of ±1% yield over 2 runs.

Example 9—Automated Synthesis of 4-[¹⁸F]Fluoroanisole

4-[¹⁸F]Fluoroanisole was prepared by the general procedure for automatedsynthesis of ¹⁸F-labeled compounds described in Example 3 with 1500 mCiinitial activity of ¹⁸F. Under automated conditions, [4-OMePh-I-Mes]BF₄was converted to 4-[¹⁸F]fluoroanisole in a radiochemical yield (RCY) of40±10% and a specific activity (SA) of 1800±800 Ci/mmol (n=3).Additionally, [4-OMePh-I-Mes]OTs was converted to 4-[¹⁸F]fluoroanisolein a radiochemical yield (RCY) of 10±2% with a SA of 3000±1000 Ci/mmol(n=3). These results indicated that isotopic dilution via ¹⁸F/¹⁹Fexchange between the [¹⁹F]BF₄ ⁻ counterion and the [¹⁸F]KF is notsignificant under these reaction conditions.

Example 10—[¹⁸F]Fluorination of Mesityl Aryliodonium Salts

Mesityl aryliodonium salts were converted to [¹⁸F]-labeled compounds bythe general procedure for manual synthesis of ¹⁸F-labeled compoundsdescribed in Example 2, except that the copper catalyst, diaryliodoniumsalt, and reaction conditions were as shown in Table 6.

TABLE 6 [¹⁸F]Fluorination of Mesityl Aryliodonium Salts

Example Mesityl Aryliodonium Precursor Product RCY* 10a^(†)

79 ± 8% (n = 38) 10b^(†)

51 ± 6% (n = 5) 10c^(†)

14 ± 1% (n = 5) 10d^(†)

30 ± 8% (n = 6) 10e^(†)

66 ± 2% (n = 3) 10f^(†)

51 ± 8% (n = 3) 10g^(†)

67 ± 2% (n = 3) 10h^(†)

35 ± 8% (n = 3) 10i^(†)

58 ± 4% (n = 3) 10j^(†)

35 ± 1% (n = 3) *Radiochemical Yield (RCY) was determined by radio-TLC(average of n runs). The identity of each product was confirmed by HPLC.^(†)Conditions: Precursor (6 μmol), [Cu] (6 μmol), [¹⁸F]KF•18-crown-6 inDMF (250 μL, 300-700 μCi), total volume 750 μL.

All of the reactions in Table 6 were highly selective for a single¹⁸F-containing product, with ≤2% fluoromesitylene detected.Additionally, for each of the substrates, ≤2% of the correspondingfluoroarene product was observed in the absence of Cu catalyst.

As demonstrated in Table 1, arenes containing multiple electron-donatingmethoxy substituents were converted to the corresponding[¹⁸F]fluorinated compound (Examples 10b and 10c). Also as demonstratedin Table 1, electron neutral and electron deficient aryl rings wereconverted to the corresponding [¹⁸F]fluorinated compound (Examples 10f,10g, 10h, 10i, and 10j). Additionally as demonstrated in Table 1, arylrings having a variety of functional groups including amides, ketones,iodides, esters, and aldehydes were converted to the corresponding[¹⁸F]fluorinated compound (Examples 10e, 10g, 10h, 10i, and 10j).

Example 11—Synthesis of(Mesityl)(N-(Tert-Butylcarbonyl)-3,4-Di(Methoxy)-L-Phenylalanine MethylEster)-2-Iodonium Tosylate

(Mesityl)(N-(tert-butylcarbonyl)-3,4-di(methoxy)-L-phenylalanine methylester)-2-iodonium tosylate was prepared by the following 6 stepsynthesis.

Steps 1 and 2. Synthesis ofN-(tert-butylcarbonyl)-3,4-di(tertbutylcarbonyl)-L-phenylalanine methylester. To an ice cold solution of L-DOPA (3.34 g, 17 mmol, 1.0 equivAcros) in MeOH (50 mL), SOCl₂ (1.5 mL, 21 mmol, 1.2 equiv) was addeddropwise. The solution was slowly warmed to 50° C. After 22 h, thereaction mixture was concentrated under vacuum. To remove volatilebyproducts, the mixture was re-dissolved in MeOH and re-concentrated.EtOAc (25 mL) was then added, and the solution was re-concentrated undervacuum to remove residual MeOH. The crude DOPA-NH₃Cl—OMe was used in thenext step without further purification.

An aliquot of the oil prepared above (1.3 g, assume 5.2 mmol) wasdissolved in pyridine (10 mL, 124 mmol) at room temperature. Pivaloylchloride (4 mL, 32 mmol) was added dropwise. After 20 h at roomtemperature, the solution was poured onto 2M HCl. The resulting solutionwas extracted with EtOAc (3×20 mL). The combined organic layers werewashed with water, washed with brine, dried over Na₂SO₄, filtered, andconcentrated under vacuum. Final purification via flash chromatography(100 g Biotage® SNAP silica column, gradient from 0% to 100% EtOAc inhexanes, R_(f)=0.4 in 30% EtOAc in hexanes) afforded ofN-(tert-butylcarbonyl)-3,4-di(tertbutylcarbonyl)-L-phenylalanine methylester as an oil (2.2 g, 15.3 mmol, 90% yield over two steps).

Step 3.N-(tert-butylcarbonyl)-2-iodo-3,4-di(tertbutylcarbonyl)-L-phenylalaninemethyl ester was prepared by the following procedure adapted from theliterature (Lee, E., J. Am. Chem. Soc., 134:17456 (2012)). A solution ofN-(tert-butylcarbonyl)-3,4-di(tertbutylcarbonyl)-L-phenylalanine methylester (2.20 g, 4.8 mmol, 1.0 equiv) in CH₂Cl₂ (50 mL) was cooled in anice bath. To this solution, solid molecular iodine (1.51 g, 6.4 mmol,1.3 equiv) was added followed by solid[bis(trifluoroacetoxy)iodo]benzene (2.5 g, 5.8 mmol, 1.2 equiv). Thesolution was allowed to slowly warm to room temperature. After 24 h, thereaction was quenched by the addition of an aqueous solution of Na₂S₂O₃,and the deep red color of iodine rapidly faded. The resulting solutionwas extracted with CH₂Cl₂ (3×20 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under vacuum. Finalpurification via flash chromatography (100 g Biotage® SNAP silicacolumn, gradient from 0% to 100% EtOAc in hexanes, R_(f)=0.5 in 30%EtOAc in hexanes) affordedN-(tert-butylcarbonyl)-2-iodo-3,4-di(tertbutylcarbonyl)-L-phenylalaninemethyl ester as an oil (337 mg, 3.9 mmol, 81% yield).

Step 4. Synthesis ofN-(tert-butylcarbonyl)-2-iodo-3,4-di(methoxy)-L-phenylalanine methylester. A flask was charged withN-(tert-butylcarbonyl)-2-iodo-3,4-di(tertbutylcarbonyl)-L-phenylalaninemethyl ester (545 mg, 0.92 mmol, 1.0 equiv), and it was brought insideof a glove box. Sodium methoxide (113 mg, 2.1 mmol, 2.3 equiv) was addedas a solid. The solids were then dissolved in DMF (6 mL) at roomtemperature, and the flask was sealed and removed from the glove box.After 2 h, methyl iodide (0.2 mL, 3.2 mmol, 3.5 equiv) was added viasyringe. After an additional 2 h at room temperature, the reaction wasquenched by the addition of water. The resulting solution was extractedwith EtOAc (3×20 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under vacuum. Final purification viaflash chromatography (25 g Biotage® SNAP silica column, gradient from 0%to 100% EtOAc in hexanes, R_(f)=0.5 in 30% EtOAc in hexanes) affordedN-(tert-butylcarbonyl)-2-iodo-3,4-di(methoxy)-L-phenylalanine methylester as an oil (337 mg, 0.75 mmol, 81% yield).

Step 5. Synthesis ofN-(tert-butylcarbonyl)-2-trimethylstannyl-3,4-di(methoxy)-L-phenylalaninemethyl ester. A 20 mL vial was charged withN-(tert-butylcarbonyl)-2-iodo-3,4-di(methoxy)-L-phenylalanine methylester (335 mg, 0.75 mmol, 1.0 equiv), and it was brought inside of aglove box. Lithium chloride (151 mg, 3.6 mmol, 4.8 equiv) and Pd(PPh₃)₄(172 mg, 0.15 mmol, 0.2 equiv) were added as solids. The combined solidswere then dissolved in PhMe (10 mL) at room temperature. Hexamethylditin(0.8 mL, 3.9 mmol, 5.2 equiv) was added via syringe, and the vial wassealed and removed from the glove box. The sealed vial was heated to100° C. The initially yellow solution turned black during the course ofthe reaction. After 2 h, the vial was cooled to room temperature, andthe solution was filtered through celite and concentrated under vacuum.Final purification via flash chromatography (25 g Biotage® SNAP silicacolumn, gradient from 0% to 100% EtOAc in hexanes, R_(f)=0.5 in 30%EtOAc in hexanes) affordedN-(tert-butylcarbonyl)-2-trimethylstannyl-3,4-di(methoxy)-L-phenylalaninemethyl ester as a light yellow oil (249 mg, 0.51 mmol, 68% yield).

Step 6. Synthesis of(mesityl)(N-(tert-butylcarbonyl)-3,4-di(methoxy)-L-phenylalanine methylester)-2-iodonium tosylate was accomplished by following a procedureadapted from the literature (Chun, J. H., J. Org. Chem., 77:1931(2012)). A 20 mL vial was charged with a solution ofN-(tert-butylcarbonyl)-2-trimethylstannyl-3,4-di(methoxy)-L-phenylalaninemethyl ester (247 mg, 0.51 mmol, 1.0 equiv) in CH₂Cl₂ (10 mL). SolidMesI(OH)(OTs) (254 mg, 0.59 mmol, 1.2 equiv) was added at roomtemperature. After 50 min, the solution was concentrated under a streamof nitrogen. Final purification via flash chromatography (25 g Biotage®SNAP silica column, gradient from 0% to 100% iPrOH in CH₂Cl₂, R_(f)=0.5in 10% iPrOH in CH₂Cl₂) afforded(mesityl)(N-(tert-butylcarbonyl)-3,4-di(methoxy)-L-phenylalanine methylester)-2-iodonium tosylate as a colorless oil (233 mg, 0.32 mmol, 62%yield). The oil could be solidified by dissolving it in CH₂Cl₂ followedby the slow addition of hexanes. The mixture of solvents was thenremoved under vacuum to afford a white solid.

Example 12—Synthesis of Protected 4-[¹⁸F]Fluoro-_(L)-Phenylalanine,Protected 3-[¹⁸F]Fluorotyrosine, and Protected 6-[¹⁸F]Fluoro-_(L)-DOPA

Protected 4-[¹⁸F]fluoro-_(L)-phenylalanine, protected3-[¹⁸F]fluorotyrosine, and protected 6-[¹⁸F]fluoro-_(L)-DOPA wereprepared by the general procedure for manual synthesis of ¹⁸F-labeledcompounds described in Example 2, except that the copper catalyst,diaryliodonium salt, and reaction conditions were as shown in Table 7.

TABLE 7 Synthesis of Protected 4-[¹⁸F]Fluoro-_(L)-Phenylalanine,Protected 3- [¹⁸F]Fluorotyrosine, and Protected 6-[¹⁸F]Fluoro-_(L)-DOPAExample Mesityl Aryliodonium Salt Product RCY* 12a^(†)

23 ± 6% (n = 3) 12b^(†)

14 ± 2% (n = 3) 12c^(†)

17 ± 6% (n = 3) *Radiochemical Yield (RCY) was determined by radio-TLC(average of n runs). The identity of each product was confirmed by HPLC.^(†)Conditions: Mesityl aryliodonium salt (6 μmol), (CH₃CN)₄CuOTf (6μmol), [¹⁸F]KF•18-crown-6 in DMF (250 μL, 300-700 μCi), total volume 750μL, 85° C., 20 min.

As demonstrated in Table 7, mesityl aryliodonium salts were converted tothe corresponding [¹⁸F]fluorinated compounds, i.e., acetyl-protected4-[¹⁸F]fluoro-_(L)-phenylalanine, acetyl-protected3-[¹⁸F]fluorotyrosine, and pivaloyl-protected 6-[¹⁸F]fluoro-_(L)-DOPA(Examples 12a, 12b, and 12c).

Pivaloyl-protected 6-[¹⁸F]fluoro-_(L)-DOPA was prepared by the generalprocedure for automated synthesis of ¹⁸F-labeled compounds described inExample 3 with 1500 mCi initial activity of ¹⁸F. Under automatedconditions, the mesityl aryliodonium salt shown in Example 12c wasconverted to pivaloyl-protected 6-[¹⁸F]fluoro-_(L)-DOPA in aradiochemical yield (RCY) of 17±2% (ca. 60 mCi) and a (SA) of 4000±2000Ci/mmol (n=2).

The present invention is described in connection with preferredembodiments. However, it should be appreciated that the invention is notlimited to the disclosed embodiments. It is understood that, given thedescription of the embodiments of the invention herein, variousmodifications can be made by a person skilled in the art. Suchmodifications are encompassed by the claims below.

What is claimed is:
 1. A method of preparing a radiolabeled arylfluoride of Formula (2) comprising: reacting a diaryliodonium salt ofFormula (1)

with an ¹⁸F source in the presence of a copper (I) source selected fromCuOTf.toluene and (CH₃CN)₄CuOTf under conditions sufficient to form theradiolabeled aryl fluoride of Formula (2)

wherein Ar¹ and Ar² independently are aryl groups; and X⁻ is an anion.2. The method of claim 1, wherein Ar¹ has a structure of Formula (3):

wherein R¹, R², and R³ are independently selected from the groupconsisting of H, C₁₋₄alkyl, OR^(a), NR^(a)R^(b), halo,—NR^(a)C(═O)R^(b), —C(═O)NR^(a)R^(b), —OC(═O)R^(a), —C(═O)OR^(a),—C(═O)R^(a), aryl, benzyl, and

or R² and R³, taken together with the carbon atoms to which they areattached, form a 4- to 8-membered ring; R^(a) is selected from the groupconsisting of H, C₁₋₄alkyl, aryl, and benzyl; and R^(b) is selected fromthe group consisting of H, C₁₋₄alkyl, aryl, benzyl, —O—C₁₋₄alkyl,—O-aryl, and —O-benzyl; with the proviso that at least one of R¹, R²,and R³ is other than H.
 3. The method of claim 2, wherein R² and R³,taken together with the carbon atoms to which they are attached, form asubstituted 4- to 8-membered ring.
 4. The method of claim 1, wherein Ar¹is selected from the group consisting of:


5. The method claim 1, wherein Ar² has a structure of Formula (4):

wherein each R⁴ is independently selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, aryl, and benzyl; and n is selected from the group consistingof 1, 2, 3, 4, and
 5. 6. The method of claim 5, wherein Ar² is


7. The method of claim 1, wherein Ar² is


8. The method of claim 1, wherein the diaryliodonium ion is selectedfrom the group consisting of


9. The method of claim 1, wherein X⁻ is selected from the groupconsisting of fluoride, chloride, bromide, iodide,trifluoromethanesulfonate, toluene sulfonate, tetrafluoroborate,hexafluorophosphate, methanesulfonate, hexafluoropropanesulfonate,nonafluorobutanesulfonate, nitrophenyl sulfonate, bromophenyl sulfonate,perfluoroalkyl sulfonate, tetraphenylborate, trifluoroacetate,perfluoroalkylcarboxylate, perchlorate, hexafluorostibate,hexachlorostibate, acetate, and benzoate.
 10. The method of claim 1,wherein X⁻ is BF₄ ⁻.
 11. The method of claim 1, wherein the ¹⁸F sourceis selected from the group consisting of ¹⁸F-labeled alkali metalfluorides, ¹⁸F-labeled alkaline earth metal fluorides, ¹⁸F-labeledammonium fluorides, and complexes thereof.
 12. The method of claim 1,wherein the ¹⁸F source is selected from the group consisting of ¹⁸Flithium fluoride, ¹⁸F sodium fluoride, ¹⁸F potassium fluoride, ¹⁸Frubidium fluoride, ¹⁸F cesium fluoride, ¹⁸F beryllium fluoride, ¹⁸Fmagnesium fluoride, ¹⁸F calcium fluoride, ¹⁸F-labeled tetraalkylammoniumfluorides, and complexes thereof.
 13. The method of claim 1, wherein the¹⁸F source is selected from the group consisting of ¹⁸F potassiumfluoride and ¹⁸F potassium fluoride.18-crown-6 complex.
 14. The methodof claim 1, wherein the ¹⁸F source comprises a complex with a crownether, optionally wherein the crown ether is selected from the groupconsisting of 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6,and diaza-18-crown-6.
 15. The method of claim 1, wherein the reacting iscarried out at a temperature of about 80° C. to about 90° C.
 16. Themethod claim 1, wherein the reacting is carried out at a molar ratio ofthe copper (I) source to the diaryliodonium salt of about 1:20 to about5:1, about 1:10 to about 3:1, about 1:5 to about 2:1, and/or about 1:2to 1:1.
 17. The method of claim 1, wherein the reacting is carried outin a polar aprotic solvent.
 18. The method of claim 1, wherein thereacting is carried out in a solvent selected from the group consistingof acetone, methyl ethyl ketone, isophorone, dichloromethane,chloroform, ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide(DMSO), tetrahydrofuran (THF), acetonitrile, and mixtures thereof. 19.The method of claim 1, further comprising isolating the radiolabeledaryl fluoride of Formula (2).
 20. The method of claim 1, wherein thecopper (I) source is (CH₃CN)₄CuOTf.
 21. The method of claim 1, wherein Xis PF₆ ⁻ or OTs⁻.